NUC-1031
Gemcitabine (1; marketed as Gemzar®) is an effective nucleoside analogue that is currently approved to treat breast, non-small cell lung, ovarian and pancreatic cancers and widely used to treat a variety of other cancers including bladder, biliary, colorectal and lymphoma.

Gemcitabine's clinical utility is limited by a number of inherent and acquired resistance mechanisms. At the cellular level resistance is dependent on three parameters: (i) the down-regulation of deoxycytidine kinase, necessary for the activation into the phosphorylated moiety; (ii) the reduced expression of nucleoside transporters, in particular, hENT1 required for uptake by cancer cells; and (iii) the up-regulation of catalytic enzymes especially cytidine deaminase that degrades gemcitabine.
WO2005/012327 describes a series of nucleotide prodrugs for gemcitabine and related nucleoside drug molecules. Among them gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate (NUC-1031; 2) is identified as a particularly effective compound. These prodrugs appear to avoid many of the inherent and acquired resistance mechanisms which limit the utility of gemcitabine (‘Application of ProTide Technology to Gemcitabine: A Successful Approach to Overcome the Key Cancer Resistance Mechanisms Leads to a New Agent (NUC-1031) in Clinical Development’; Slusarczyk et all; J. Med. Chem.; 2014, 57, 1531-1542).
NUC-1031 2 is typically prepared as a mixture of two diastereoisomers, epimeric at the phosphate centre (the S-epimer 3 and the R-epimer 4) which can be separated and administered as a single epimer.

ProGem1 was a first-time-in-human (FTIH), phase I, open label, two stage study to investigate the safety, tolerability, clinical efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of NUC-1031 given in two parallel dosing schedules in subjects with advanced solid malignancies (EudraCT Number: 2011-005232-26). Subjects had the following tumour types at study entry: colorectal cancer (3 subjects), unknown primary (3), ovarian cancer (4), breast cancer (2), pancreatic cancer (3), cholangiocarcinoma (2), uterine or endometrial cancer (3), cervix cancer (1), lung cancer (2), mesothelioma (3) and thyroid cancer (1). The study confirmed NUC-1031's anti-tumour activity in patients with advanced progressive cancers, who have exhausted all standard therapeutic options, many of whom were resistant or refractory to prior nucleoside analogue therapy, including gemcitabine. Of particular note, the pharmacokinetic data showed that NUC-1031 as single agent generates around 10-fold higher Cmax intracellular levels of the active triphosphate moiety (dFdCTP) than single agent gemcitabine at equimolar dose. Moreover the analyses revealed that NUC-1031 releases less than half the levels of the toxic metabolite normally associated with gemcitabine.
Ovarian Cancer
Ovarian cancer is the sixth most commonly diagnosed cancer among women worldwide with an estimated 204,000 new cases diagnosed each year. The mortality rate is high with a 5 year survival rate of 45%, primarily because many women present with late stage disease but also because there is a high rate of disease recurrence and development of platinum-resistance. The initial therapy for advanced stage ovarian cancer is a combination of optimal surgical debulking and systemic treatment with a platinum plus taxane chemotherapy regimen. Even though complete response following treatment is observed in 70%, the majority will subsequently present with disease relapse within 2 years.
Therapy for recurrent disease is governed by the time between primary treatment and relapse. This is defined as the platinum-free interval (PFI): (1) Those with disease progression while receiving platinum-based therapy or within 4 weeks of last platinum dose are defined as having platinum-refractory disease; (2) those with a PFI of >1 month and less than 6 months have platinum-resistant disease; (3) those with a PFI of 6-12 months have partial platinum resistance; (4) and those with PFI>than 12 months have platinum-sensitive recurrence. According to NICE guidelines, those with platinum-resistant or refractory disease should then be treated with topotecan, liposomal doxorubicin, weekly paclitaxel or entered into a clinical study. Those with partially platinum-resistant recurrence should be treated with platinum-based regimens such as carboplatin with gemcitabine, carboplatin with liposomal doxorubicin or entered into a clinical study. Those with platinum-resistant disease should be retreated with carboplatin, either as monotherapy or in combination with paclitaxel. Unfortunately, those with platinum-resistant recurrence have a significantly shorter median overall survival (35 to 61 weeks) compared to those with platinum-sensitive disease (>104 weeks) suggesting that response to platinum is a key determinant for survival.
Chemotherapy Resistance in Ovarian Cancer
An almost inevitable result of repeated exposure to courses of platinum-based chemotherapy is the development of platinum resistance. This occurs via a number of mechanisms such as up-regulation of DNA damage repair and anti-apoptosis proteins, reduced copper transporters and increased drug efflux from the cancer cell. A rationale for combining platinum-based chemotherapy (such as carboplatin) with another chemotherapy agent, such as gemcitabine or liposomal doxorubicin, is to overcome resistance and improve sensitivity to platinum. Certainly, response to carboplatin alone in partially platinum resistant recurrence is inferior in comparison to when carboplatin is given in combination with gemcitabine or liposomal doxorubicin. Although the response to combination therapy is superior to platinum monotherapy, the overall prognosis for these patients is very poor and novel treatment strategies are needed for this population.
Gemcitabine in Ovarian Cancer
Gemcitabine in combination with platinum (e.g. carboplatin) is effective for relapsed ovarian cancer, even following previous platinum exposure, due to the ability of gemcitabine to reverse resistance associated with enhanced DNA repair. In the AGO-OVAR study 356 patients with platinum sensitive recurrent ovarian cancer were assigned to either carboplatin AUC5 alone or carboplatin AUC4 (day 1) plus gemcitabine 1000 mg/m2 on days 1 & 8 every 3 weeks. After a median follow-up of 17 months, a median PFS of 8.6 months was observed (95% CI, 7.9 to 9.7 months) for gemcitabine plus carboplatin and 5.8 months (95% CI, 5.2 to 7.1 months) for carboplatin alone (HR 0.72 (95% CI, 0.58 to 0.90; P=0.0031)). A response rate of 47.2% (95% CI, 39.9% to 54.5%) was recorded for gemcitabine plus carboplatin and 30.9% (95% CI, 24.1% to 37.7%) for carboplatin alone (P=0.0016). In view of the improved response and survival, gemcitabine is usually given alongside carboplatin in the relapsed, platinum-sensitive setting.
The combination of carboplatin AUC4 (day 1) and gemcitabine 1000 mg/m2 on (days 1 & 8) every 3 weeks was trialled in the control arm of the OCEANS study, a randomised study in patients with platinum-sensitive ovarian cancer. 242 patients received this combination and demonstrated an objective response rate of 57.4%, 48.3% partial response and a duration of response of 7.4 months. In women with platinum-resistant recurrence, gemcitabine given alongside carboplatin was shown in one study to have a global response rate of 47%. However, in view of the likely resistance to carboplatin and relatively poor cellular uptake of gemcitabine in these patients, other non-platinum regimens are generally favoured over carboplatin and gemcitabine.
It is an aim of this invention to provide a combination therapy for treating cancer. It is an aim of this invention to provide a therapy that is more effective than existing treatments.
Certain embodiments of this invention satisfy some or all of the above aims.